A phase Ib study of porustobart (HBM4003), an anti-CTLA-4 heavy chain only monoclonal antibody, in combination with toripalimab in patients with hepatocellular carcinoma.
Authors: Ningning Zhang, Shukui Qin, Yabing Guo, Zhongyuan Xu, Yanqiao Zhang, Jun Yao, Shanzhi Gu, Jie Shen, Aibing Xu, Yajin Chen, Guijie Xin, Ge Yu, Gang Wang, Jingdong Zhang, Humphrey Gardner, Luyin Ding, Shuai Zhao, Dian Yang, Wei Lu, Jihui Hao
Journal: Journal of Clinical Oncology (2023)

e16106 Background: Porustobart (HBM4003) is a fully human heavy chain only monoclonal antibody (HCAb) targeting CTLA-4. In addition to blocking the CTLA-4 pathway, it has been shown to effectively deplete intratumoral T reg cells in patients due to its engineered enhanced antibody-dependent cellular cytotoxicity (ADCC). Toripalimab is a recombinant, humanized anti-PD-1 monoclonal antibody. Here we reported the results of a phase Ib study that evaluated porustobart plus toripalimab in patients with hepatocellular carcinoma (HCC). Methods: This is a phase Ib dose expansion study (NCT05149027). Patients with advanced HCC (n=28) received porustobart 0.45 mg/kg plus toripalimab 240 mg every three weeks (Q3W) in both Cohort 1 and Cohort 2. Cohort 1 recruited pts who failed previous anti-VEGFR multikinase inhibitor(s) treatment while have not received anti-PD-(L)1 treatment (n=16); Cohort 2 recruited patients who failed previous anti-PD-(L)1 and anti-VEGF(R) treatments (n=12). The primary endpoint was ORR per RECIST 1.1. Results: As of 9 Dec 2022, median follow-up time was 3.6 months (range: 1-7 months). In Cohort 1, ORR and DCR were 46.7% (95%CI: 21.3-73.4) and 73.3% (95%CI: 44.9-92.2) respectively in 15 patients with post-treatment tumor assessments. In Cohort 2, the ORR and DCR were 9.1% (95%CI: 0.2-41.3) and 54.5% (95%CI: 23.4-83.3) respectively in 11 patients with post-treatment tumor assessments. PFS or OS data were not mature by the cut-off date. Treatment-related adverse events (TRAEs) were reported in 89.3% (25/28) patients, and Grade 3 TRAEs were reported in 39.3% (11/28) patients. The most common (≥20%) TRAEs with all grades by pooled term were liver function test abnormal 46.4% (13/28), thrombocytopenia 42.9% (12/28), pyrexia 32.1% (9/28), asthenia 28.6% (8/28), anemia 25% (7/28), decreased appetite 25% (7/28), blood bilirubin increased 21.4% (6/28), leucopenia 21.4% (6/28), lymphopenia 21.4% (6/28), nausea 21.4% (6/28) and neutropenia 21.4% (6/28). TRAEs leading to permanent discontinuation of porustobart were reported in 3 (10.7%) patients. No Grade 4 or Grade 5 TRAE was reported. Porustobart promoted the clearance of T reg cells and the proliferation of CD4 + T cells and CD8 + T cells in peripheral blood that attested to its MOA. Greater effects were observed in Cohort 1. Taken together with the clinical observations these results suggested that PD-(L)1 inhibitor naïve patients have a larger available pool of effectors to induce anti-tumor activity in the presence of effective T reg depletion. No noticeable differences in PK between Cohort 1 and Cohort 2 were observed. Conclusions: Porustobart 0.45 mg/kg in combination with toripalimab 240mg Q3W showed promising anti-tumor activity in patients with advanced HCC, as well as an acceptable safety profile. Clinical trial information: NCT05149027 .